Studies on the Synthesis of Apoptolidin
FULL PAPER
4
3
.13–4.06 (m, 1 H), 3.43 (dd, J = 10.0, 4.0 Hz, 1 H), 3.27 (s, 3 H),
.25 (dd, J = 9.0, 6.0 Hz, 1 H), 3.14 (dd, J = 9.0, 5.0 Hz, 1 H), 3.1
(125 MHz, C
6
D
6
): δ = 169.9, 169.6, 169.2, 141.7, 135.8, 133.9,
132.1, 128.2, 101.9, 88.7, 78.4, 78.0, 76.1, 75.0, 71.4, 71.1, 70.3,
69.5, 67.3, 58.7, 57.1, 45.7, 39.2, 37.3, 34.4, 34.2, 27.9, 26.1, 25.7,
25.0, 20.8, 20.4, 20.2, 18.3, 17.8, 13.7, 12.5, 11.8, 7.0, 5.7, 5.2,
–3.3, –4.0, –4.0, –5.3. HRMS (ESI): m/z = 1191.4857 ([M + Li]
2 3
calculated for C53H98Br LiO13Si : 1191.4842).
(
(
(
(
(
s, 3 H), 2.25 (dd, J = 15.0, 11.0 Hz, 1 H), 2.20–2.08 (m, 3 H), 2.14
s, 3 H), 1.98–1.87 (m, 3 H), 1.92(s, 3 H), 1.74–1.56 (m, 2 H), 1.63
s, 3 H), 1.62 (s, 3 H), 1.46 (ddd, J = 14.0, 10.5, 2.0 Hz, 1 H), 1.22
d, J = 6.5 Hz, 3 H), 1.03 (d, J = 7.0 Hz, 3 H), 1.03 (s, 9 H), 0.93
s, 9 H), 0.33 (s, 3 H), 0.32 (s, 3 H), 0.23 (s, 3 H), 0.11 (s, 3 H).
): δ = 170.1, 169.7, 169.3, 140.6, 102.0, 94.3,
8.5, 78.1, 75.1, 71.5, 71.2, 70.4, 69.5, 67.4, 58.9, 57.2, 39.4, 37.4.
+
1
3
C
Glycoside 23: To a solution of alcohol (0.008 g, 7.53 μmol) and gly-
cosyl sulfide 24 (0.0075 g, 15.0 μmol) in DCM (1 mL) at –20 °C
was added 4-Å molecular sieves. A solution of TESOTf in DCM
6 6
NMR (125 MHz, C D
7
3
1
4.5, 34.4, 37.7, 37.4, 27.3, 26.2, 25.8, 21.0, 20.5, 20.3, 18.4, 18,
1.9, 5.8, –3.3, –4.0, –4.0, –5.2. HRMS (ESI): m/z = 953.3709 ([M
(
0.1 mL, 7.5 mmol) was then added dropwise. The resulting solu-
tion turned to pink and was quenched with saturated Na after
0 min. The aqueous layer was extracted with DCM (3×30 mL).
2 2 3
S O
+
+
Na] calculated for C40
H75INaO12Si12: 953.3739).
1
Aldehyde 21: To a solution of acetate 4 (0.10 g, 0.107 mmol) and
boronic ester 20 (0.080 g, 0.225 mmol) in THF/H O (3.6 mL, 3:1,
degassed) at room temperature was added [Pd(Ph P) ] (0.012 g,
.011 mmol). The resulting yellow solution was stirred 5 min before
TlOEt (0.011 mL, 0.161 mmol) was added via syringe. The reaction
was stirred for 40 min and quenched with 1 n NaHSO (4 mL). The
mixture was filtered through Celite and rinsed with EtOAc
60 mL). The organic layer was separated, dried (MgSO ), filtered
4
The combined organic layers were dried (MgSO ), filtered and con-
centrated in vacuo. The residue was purified by flash chromatog-
2
3
4
raphy (hexanes/EtOAc, 10:1) to afford 0.005 g (45%) of the α-gly-
1
0
coside 23 as a colorless oil: H NMR (500 MHz, C
6
D
6
): δ = 6.29
(d, J = 15.5 Hz, 1 H), 6.24 (d, J = 9.5 Hz, 1 H), 5.53–5.46 (m, 4
H), 5.38 (dt, J = 10.0, 3.5 Hz, 1 H), 5.33 (s, 1 H), 4.93 (d, J =
3.5 Hz, 1 H), 4.72 (d, J = 9.0 Hz, 1 H), 4.42 (dd, J = 9.5, 5.0 Hz,
1 H), 4.21–4.13 (m, 2 H), 4.08 (dd, J = 9.0, 6.0 Hz, 1 H), 3.89–3.85
(m, 1 H), 3.67 (dd, J = 9.5, 3.5 Hz, 1 H), 3.52 (dd, J = 11.5, 4.0 Hz,
1 H), 3.34 (s, 3 H), 3.33 (s, 3 H), 3.29 (dd, J = 9.0, 6.5 Hz, 1 H),
3.21 (dd, J = 9.0, 4.5 Hz, 1 H), 3.14 (s, 3 H), 2.84–2.78 (m, 1 H),
2.67 (t, J = 9.0 Hz, 1 H) 2.36–2.16 (m, 5 H), 2.14–2.08 (m, 1 H),
1.96 (s, 3 H), 1.96–1.92 (m, 1 H), 1.84–1.70 (m, 2 H), 1.80 (s, 3 H),
1.66 (s, 3 H), 1.54–1.50 (m, 1 H), 1.40–1.28 (m, 6 H), 1.38 (d, J =
6.0 Hz, 3 H), 1.25 (d, J = 6.5 Hz, 3 H), 1.20–1.15 (m, 9 H), 1.09–
1.06 (m, 18 H), 0.97–0.85 (m, 18 H), 0.68 (q, J = 8.0 Hz, 6 H), 0.36
4
(
4
and concentrated in vacuo. The residue was purified by flash
chromatography (hexanes/EtOAc, 10:1) to afford 0.098 g (88%) of
1
aldehyde 21 as a colorless oil: H NMR (500 MHz, C
6
D
6
): δ = 9.68
(d, J = 1.0 Hz, 1 H), 6.25 (d, J = 15.5 Hz, 1 H), 5.53 (dd, J = 16.0,
7.0 Hz, 1 H), 5.52–5.49 (m, 2 H), 5.47 (t, J = 4.5 Hz, 1 H), 5.37
(dt, J = 10.0, 3.5 Hz, 1 H), 5.32 (s, 1 H), 4.71 (d, J = 9.0 Hz, 1 H),
4
4
3
.47 (dd, J = 6.5, 3.5 Hz, 1 H), 4.42 (dd, J = 9.0, 5.5 Hz, 1 H),
.19–4.16 (m, 1 H), 3.51 (dd, J = 10.5, 3.5 Hz, 1 H), 3.33 (s, 3 H),
.29 (dd, J = 9.0, 6.5 Hz, 1 H), 3.19 (dd, J = 9.5, 4.5 Hz, 1 H), 3.12
1
3
(s, 3 H), 0.35 (s, 3 H), 0.26 (s, 3 H), 0.15 (s, 3 H). C NMR
): δ = 170.0, 169.6, 169.3, 141.0, 140.6, 133.7,
133.4, 130.6, 123.4, 102.0, 95.2, 89.5, 87.6, 78.4, 77.9, 75.0, 74.6,
s, 9 H), 1.05 (q, J = 8.0 Hz, 6 H), 0.97 (t, J = 8.0 Hz, 9 H), 0.95 74.5, 71.6, 71.1, 70.3, 69.6, 68.1, 67.3, 60.9, 58.8, 57.2, 43.8, 39.3,
s, 9 H), 0.57 (q, J = 8.0 Hz, 9 H), 0.36 (s, 3 H), 0.35 (s, 3 H), 0.26 37.4, 34.4, 34.3, 32.2, 30.1, 29.7, 26.1, 25.7, 23.0, 20.9, 20.4, 20.2,
s, 3 H), 0.14 (s, 3 H). 13C NMR (125 MHz, C
): δ = 202.6, 18.6, 18.3, 17.9, 14.6, 14.3, 12.4, 11.8, 7.4, 7.2, 5.8, 5.4, –3.3, –4.0,
(
(
(
(
(
s, 3 H), 2.37–2.15 (m, 6 H), 1.94 (s, 3 H), 1.86–1.74 (m, 2 H), 1.68 (125 MHz, C
s, 3 H), 1.66 (s, 3 H), 1.64 (s, 3 H), 1.24 (d, J = 6.5 Hz, 3 H), 1.06
6 6
D
6
D
6
1
7
3
1
1
69.9, 169.6, 169.2, 136.0, 133.8, 132.4, 127.5, 101.9, 78.4, 78.0,
–4.0, –5.3.
5.0, 73.9, 71.4, 71.2, 70.4, 69.5, 67.3, 58.7, 57.1, 53.2, 39.3, 37.4,
4.5, 34.3, 28.0, 26.1, 25.7, 25.0, 20.9, 20.5, 20.2, 18.3, 17.9, 12.5,
1.9, 8.6, 7.0, 5.7, 5.2, –3.4, –4.0, –4.1, –5.3. HRMS (ESI): m/z =
Triene 26: To a solution of the dibromide 22 (0.040 g, 0.0337 mmol)
and the boronic ester 25 (0.060 g, 0.168 mmol) in THF/H O
2
(
(
1.6 mL, 3:1, degassed) at room temperature was added [Pd-
Ph P) ] (3.9 mg, 3.37 μmol). The resulting yellow solution was
053.6058 ([M + Na]+ calculated for C52
H98NaO14Si
: 1053.6162).
3
3
4
Dibromide 22: To
a
suspension of Ph
3
P–CHBr
3
(0.510 g,
stirred 5 minutes before TlOEt (4.3 μL, 0.061 mmol) was added via
syringe. The reaction was stirred for 3 h and quenched with 1 n
0
0
5
.99 mmol) in THF (10 mL) at 0 °C was added KOtBu (0.055 g,
.50 mmol). The resulting orange solution was stirred at 0 °C for
min and a solution of aldehyde 21 (0.085 g, 0.0825 mmol) in THF
NaHSO
washed with EtOAc (30 mL). The organic layer was separated,
dried (MgSO ), filtered and concentrated in vacuo. The residue was
4
. The mixture was filtered through a Celite plug and
(
0
2 mL) was added via cannula. The reaction mixture was stirred at
°C for 30 min and quenched with brine. The aqueous layer was
extracted with Et O (3×30 mL). The combined organic layers were
dried (MgSO ), filtered and concentrated in vacuo. The residue was
purified by flash chromatography (hexane/EtOAc, 10:1) to afford
4
purified by flash chromatography (hexanes/EtOAc, 11:1) to afford
1
2
0.032 g (71%) of the trienoate 26 as a colorless oil: H NMR
4
6 6
(500 MHz, C D ): δ = 7.34 (s, 1 H), 6.29 (d, J = 15.5 Hz, 1 H),
6.17 (s, 1 H), 5.74 (dd, J = 9.0, 1.0 Hz, 1 H), 5.72 (dd, J = 15.5,
7.0 Hz, 1 H), 5.50 (t, J = 7.0 Hz, 1 H), 5.46 (dd, J = 11.5, 4.5 Hz,
1 H), 5.44 (d, J = 3.5 Hz, 1 H), 5.35 (dt, J = 9.5, 3.5 Hz, 1 H), 5.30
(s, 1 H), 4.70 (d, J = 9.0 Hz, 1 H), 4.40 (dd, J = 9.0, 5.5 Hz, 1 H),
4.27 (t, J = 8.5 Hz, 2 H), 4.20 (t, J = 6.5 Hz, 1 H), 4.18–4.13 (m,1
H), 3.51 (dd, J = 10.5, 4.0 Hz, 1 H), 3.33 (s, 3 H), 3.28 (dd, J =
9.5, 6.5 Hz, 1 H), 3.19 (dd, J = 9.5, 4.5 Hz, 1 H), 3.12 (s, 3 H),
3.11–3.06 (m, 1 H), 2.35–2.14 (m, 5 H), 2.05 (d, J = 1.0 Hz, 3 H),
1.93 (s, 3 H), 1.92–1.89 (m, 1 H), 1.86 (d, J = 1.0 Hz, 3 H), 1.84–
1.75 (m, 2 H), 1.73 (s, 3 H), 1.65 (s, 3 H), 1.64 (s, 3 H), 1.53–1.47
(m, 1 H), 1.22 (d, J = 6.5 Hz, 3 H), 1.16 (d, J = 6.5 Hz, 3 H), 1.05–
25
0
2
1
5
.080 g (82%) of dibromide 22 as a colorless oil: [α]
3 6 6
.2, CHCl ). H NMR (500 MHz, C D ): δ = 6.30 (d, J = 9.5 Hz,
H), 6.22 (d, J = 15.5 Hz, 1 H), 5.55 (dd, J = 15.5, 7.0 Hz, 1 H),
.49 (t, J = 7.5 Hz, 1 H), 5.45 (dd, J = 11.5, 5.0 Hz, 1 H), 5.43 (d,
D
= +6.7 (c =
1
J = 5.0 Hz, 1 H), 5.34 (td, J = 10.0, 3.5 Hz, 1 H), 5.30 (s, 1 H),
.69 (d, J = 9.0 Hz, 1 H), 4.39 (dd, J = 9.0, 5.5 Hz, 1 H), 4.18–4.13
m, 1 H), 4.07 (t, J = 5.5 Hz, 1 H), 3.50 (dd, J = 11.5, 4.0 Hz, 1
H), 3.33 (s, 3 H), 3.28 (dd, J = 9.0, 6.5 Hz, 1 H), 3.18 (dd, J = 9.0,
4
(
4
2
2
1
1
0
0
.5 Hz, 1 H), 3.12 (s, 3 H), 2.80–2.61 (m, 1 H), 2.35–2.29 (m, 1 H),
.28–2.13 (m, 4 H), 1.93 (s, 3 H), 1.94–1.89 (m, 1 H), 1.85–1.70 (m,
H), 1.69 (s, 3 H), 1.65 (s, 3 H), 1.63 (s, 3 H), 1.49 (ddd, J = 14.0, 1.01 (m, 21 H), 0.93 (s, 9 H), 0.93–0.89 (m, 3 H), 0.64 (dq, J = 8.0,
0.5, 1.5 Hz, 1 H), 1.36–1.28 (m, 1 H), 1.22 (d, J = 6.5 Hz, 3 H), 1.0 Hz, 6 H), 0.34 (s, 3 H), 0.33 (s, 3 H), 0.24 (s, 3 H), 0.14 (s, 3
6 6
.04 (d, J = 6.0 Hz, 3 H), 1.04 (s, 9 H), 0.99 (t, J = 8.0 Hz, 9 H), H), –0.09 (s, 9 H). C NMR (125 MHz, C D ): δ = 169.9, 169.6,
1
3
.93 (d, J = 7.0 Hz, 3 H), 0.93 (s, 9 H), 0.59 (q, J = 8.0 Hz, 6 H),
.33 (s, 3 H), 0.33 (s, 3 H), 0.24 (s, 3 H), 0.17 (s, 3 H). C NMR
169.2, 168.0, 140.9, 136.5, 136.0, 135.9, 134.1,133.8, 132.0, 128.7,
128.4, 120.6, 101.9, 78.4, 78.0, 77.2, 75.0, 71.3, 71.1, 70.4, 69.5,
1
3
Eur. J. Org. Chem. 2006, 277–284
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
283